Tyrosinemia II, is a human inborn error of metabolism, due to deficient activity of hepatic tyrosine aminotransferase (TAT). It has autosomal recessive inheritance. Tryosinemia is casually related to keratitis, palmar and plantar keratosis and erosions, and possible mental retardation. Successful treatment with a low-tyrosine low-phenylalanine diet is possible. A similar hereditary disease in mink has been recently identified. The mink model has great potential for studies of the molecular mechanism of the disease. A major question is the exact molecular nature of the enzyme defect in man and mink; furthermore there is need to develop new treatments for the human disease, develop techniques for prenatal diagnosis and heterzygote determination, and understand the detailed mechanism of the epidermal and corneal damage in this disease. Since the major catabolic pathway for tyrosine is deficient in people and mink with this disorder the ability to define the quantitative contribution of various metabolic pathways to tyrosine catabolism now exists. Defining the defect in this disease will increase understanding of the mechanism of genetic defects in skin, liver and other organ systems. In the affected humans, the specific aims include: determining the metabolic pathways for exogeneous phenylalanine and tyrosine by administering orally tyrosine and phenylalanine and determining their blood and urine metabolites. Normals, heterozygotes and individuals with tyrosinemia II will be studied. Develop methods for heterozygote determination by studies the effect of phenylalanine load tests on N-acetyltyrosine and other urinary products of tyrosine. Determine tissue levels of various tyrosine metabolites in affected and normal skin to determine if specific metabolites cause tissue damage. Exact quantitative determination of metabolites will be made by gas chromatographic mass spectrometric techniques. In mink, our studies are directed at determining the nature of the genetic lesion. This will involve 1) characterization of the normal and mutant TAT-proteins, including comparison of in vivo and in vitro synthesized products 2) identification of abnormalities in the structure, function and/or regulation of TAT-specific messenger RNA 3) identification of secondary effects which are related to the post-translational modification of TAT or the abnormal nutritional state of the affected animals. Significant abnormalities found in affected animals will then be investigated for their possible expression in obligate heterozygotes.